Olanzapine increases allopregnanolone in the rat cerebral cortex

Background: The neurosteroid allopregnanolone (3 alpha-hydroxy-5 alpha-pren an-20-one) has anxiolytic and anticonvulsant properties, potentiating GABA( A) receptor chloride channel function with 20-fold higher potency than benz odiazepines. Behavioral studies demonstrate that olanzapine has anxiolyticl ike properties in animals, but the mechanism responsible for these effects is not clear. We examined the effect of acute olanzapine administration on cerebral cortical allopregnanolone and its relationship to serum progestero ne and corticosterone levels in rats. Methods. Male Sprague-Dawley rate were habituated to intraperitoneal (IP) s aline injection for 5 days. On the day of the experiment, rats were injecte d with olanzapine (0, 2.5, 5.0 or 10.0 mg/kg IP, 10-11 rats per condition). Rats were sacrificed 1 hour later, adn cerebral cortical allopregnanolone levels were measured by radioimmunoassay. Results: Olanzapine increases cerebral cortical allopregnanolone up to four fold, depending on dose. Positive correlations were observed between cerebr al cortical allopregnanolone and serum progesterone levels adn between cere bral cortical allopregnanolone and serum corticosterone levels. Conclusions: Olanzapine-induced increases in the potent GABA(A) receptor mo dulator allopregnanolone may alter GABAergic neurotransmission, possibly co ntributing to antipsychotic efficacy. If allopregnanolone alterations are l inked to psychotic symptom relief, neurosteroids may represent molecules fo r pharmacologic intervention. (C) 2000 Society of Biological Psychiatry.